Search

Long non-coding RNAs (lnc RNAs) are long single-stranded RNAs without translation potential. Lnc RNAs function in regulating epigenetic and cellular processes through various mechanisms. Nowadays, rapidly growing evidence has shown that abnormally expressed lnc RNAs were involved in various inflammation-related states or diseases. Abnormal inflammation responses contribute to reproductive pathology and play vital roles in developing most disorders of the female reproductive system. In this review, we discussed the history of nc RNAs including lnc RNAs, methodologies for lnc RNA identification, mechanisms of lnc RNA expression and regulation and mainly discussed the expression and function of lnc RNAs in the female reproductive system with special focus on the inflammation and infection pathway. By analyzing the present available studies of lnc RNA transcripts within the reproductive system and the current understanding of the biology of lnc RNAs, we have suggested the important diagnostic and therapeutic roles of lnc RNAs in the etiology of reproductive disorders. [ABSTRACT FROM AUTHOR]

Abstract: PCBP1 is a member of the hnRNP family that functions as a RNA-binding, as well as DNA-binding, protein. The detailed transcripts and translatants targeted by PCBP1 at a global level are not yet known. We undertook an investigation of transcriptional and translational profiles after overexpressing exogenous PCBP1 in SH-SY5Y cells. Our results in two independent studies showed that 601 transcripts, including 26 down-regulated transcripts and 575 up-regulated transcripts, were impacted by overexpression of exogenous PCBP1. However, 138 and 144 transcripts showed non-overlapped differential expression in each study. These altered transcripts are clustered mainly in metabolic and transcriptional regulations. Proteomic profiles detected with a two-dimensional chromatographic PF2D showed a global change of translations, mainly in a range of pI=4.96–5.76 and pI=7.96–8.36. Three predominant proteins, which were differentially less expressed in PCBP1 overexpression cells and were detected at pI=7.96–8.16, were identified as histone proteins, indicating that histone proteins are among the targets regulated by PCBP1. Our investigation has opened a new avenue for further studying the biological functions of PCBP1. [Copyright &y& Elsevier]

Abstract: The Hutchinson–Gilford progeria syndrome (HGPS or progeria) is an apparent accelerated aging disorder of childhood. Recently, HGPS has been characterized as one of a growing group of disorders known as laminopathies, which result from genetic defects of the lamin A/C (LMNA) gene. The majority of HGPS mutant alleles involve a silent mutation, c.2063C>T resulting in G608G, that generates a cryptic splicing site in exon 11 of LMNA and consequently truncates 50 amino acids near the C-terminus of pre-lamin A/C. To explore possible mechanisms underlying the development of HGPS, we began a search for proteins that would uniquely interact with progerin (the truncated lamin A in HGPS) using a yeast two-hybrid system. Four new progerin interactive partner proteins were identified that had not been previously found to interact with lamin A/C: hnRNP E1, UBC9 (ubiquitin conjugating enzyme E2I), Mel-18, and EGF1. However, using control and progeria fibroblasts, co-immunoprecipitation studies of endogenous proteins did not show differential binding affinity compared to normal lamin A/C. Thus, we did not find evidence for uniquely interacting partner proteins using this approach, but did identify four new lamin A/C interactive partners. [Copyright &y& Elsevier]

Spontaneous preterm birth (sPTB) poses significant challenges, affecting neonatal health and neurodevelopmental outcomes worldwide. The specific effects of placental trophoblasts on the pathological development of sPTB subtypes—preterm premature rupture of fetal membranes (pPROM) and spontaneous preterm labor (sPTL)—are not fully understood, making it crucial to uncover these impacts for the development of effective therapeutic strategies. Using single-nucleus RNA sequencing, we investigated transcriptomic and cellular differences at the maternal–fetal interface in pPROM and sPTL placentas. Our findings revealed distinct trophoblast compositions with pPROM characterized predominantly by extravillous trophoblasts (EVTs), while sPTL showed an abundance of syncytiotrophoblasts (STBs). Through cell differentiation and cell-to-cell communication analyses, other distinguishing factors were also found. In pPROM, heightened inflammation, oxidative stress, and vascular dysregulation with key pathways including tumor necrosis factor signaling, matrix metalloproteinase activation, and integrin-mediated cell adhesion, highlighted an invasive EVT profile potentially driven by hypoxic conditions and immune cell recruitment. In contrast, sPTL was marked by increased smooth muscle contraction, vascular remodeling, and altered signaling dynamics involving fibroblasts, including TGF-β and WNT pathways. Our study highlights the critical need to distinguish sPTB subtypes to improve diagnostic precision and therapeutic targeting. The molecular insights gained provide a foundation for future investigations aimed at functional validation of key pathways and exploration of trophoblasts on the development of sPTB. Ultimately, these findings pave the way for more personalized and effective interventions to mitigate adverse outcomes associated with preterm birth. [ABSTRACT FROM AUTHOR]

Background: Congenital heart defects (CHDs) are the most common birth defects. Assessment of the incidence, distribution, disease spectrum, and genetic deficits of fetal CHDs in China is urgently needed. Methods: A national echocardiography screening program for fetal CHDs was implemented in 92 prenatal screening–diagnostic centers in China. Findings: A total of 18,171 fetal CHD cases were identified from 2,452,249 pregnancies, resulting in 7·4/1,000 as the national incidence rate of fetal CHD. The incidences of fetal CHD in the six geographical regions, the southern, central, eastern, southwestern, northern, and northwestern, were 7·647 (CI: 7·383–7·915), 7·839 (CI: 7·680–8·000), 7·647 (CI: 7·383–7·915), 7·562 (CI: 7·225–7·907), 5·618 (CI: 5·337–5·906), and 4·716 (CI: 4·341–5·108), respectively, per 1,000 pregnancies. Overall, ventricular septal defect was the most common fetal CHD, accounting for 17.04% of screened pregnancies nationwide, and tetralogy of Fallot, the most common anomaly in the major defect of fetal CHD, was the second most common, accounting for 9.72%. A total of 76.24% cases of fetal CHD were found to be an isolated intracardiac single defect. The remaining 23.76% of cases of fetal CHD had multiple heart defects. Among all extracardiac malformations, the central nervous system (CNS) was the most common tissue with extracardiac anomalies associated with CHD, accounting for 22.89% of fetal CHD cases. Chromosomal karyotyping identified trisomy 18 as the most common chromosomal abnormality in fetal CHD. We also documented that CHD-containing syndromes could be identified with a comprehensive approach integrating prenatal ultrasound, MRI, pathological autopsy, and cytogenetics and molecular genetics. Conclusion: Implementation of prenatal echocardiography as a practically feasible platform to screen fetal CHD will reduce the financial and emotional burden of CHD, which may facilitate intrauterine and neonatal intervention of CHD. [ABSTRACT FROM AUTHOR]

Background: Early pregnancy loss (EPL) presents as sporadic or recurrent miscarriage during the first trimester. In addition to chromosomal defects, EPL may result from impairment of the placental-decidual interface at early gestational age due to gene-environmental interactions. Methods: To better understand the pathogenesis associated with this impairment, cell development in chorionic villi and decidua of different forms of EPL (sporadic or recurrent) was investigated with single-cell RNA sequencing and compared to that of normal first-trimester tissue. Results: Unique gene expression signatures were obtained for the different forms of EPL and for normal tissue and the composition of placental and decidual cell clusters in each form was established. In particular, the involvement of macrophages in the EPL phenotypes was identified revealing an immunoactive state. Conclusion: Differential gene expression and unique marker genes among cell clusters from chorionic villi and decidua of miscarried and normal pregnancies, may lead to identification of biomarker for EPL. [ABSTRACT FROM AUTHOR]

To test the utility of a preconception checklist tool in identifying preconception health needs of women in three countries; China, Lebanon and the Philippines. An academic medical center within each country participated in the development and testing of a preconception checklist tool, which was administered over a 6 month period to selected target groups in each country. The checklist provided valuable data on the preconception health of 6,530 women. Aggregated data identified common preconception health needs across all countries, including provision of modern contraceptives and adequate immunization coverage; HIV and STI screening; treatment for anemia; and counseling for maintenance of a healthy weight. A preconception checklist tool was found to be useful in distinct cultural settings. The study was a pilot. Future steps include validation and standardization of the checklist, data from which could be used to help shape preconception care policies and implementation strategies. [ABSTRACT FROM AUTHOR]

The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21–linked early-onset Alzheimer's disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26–72 years of age were to identify the magnitude of brain region–specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26–41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43–49, 51–59, and 61–72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26–41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43–49 years of age; a 28.0% maximum neuronal loss at 51–59 years of age; and a 11.0% minimum neuronal loss at 61–72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline. [ABSTRACT FROM AUTHOR]

Objective: Summarize and analyze the current research results of tinnitus-related genes, explore the potential links between the results of each study, and provide reference for subsequent studies. Methods: Collect and sort out the research literature related to tinnitus genes included in PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform before December 31, 2019. Then the relevant contents of the literature were sorted out and summarized. Results: Fifty-one articles were finally selected for analysis: 31 articles (60.8%) were classified as researches on animal models of tinnitus, and 20 (39.2%) as researches on tinnitus patients. Existing studies have shown that genes related to oxidative stress, inflammatory response, nerve excitation/inhibition, and nerve growth are differentially expressed in tinnitus patients or animal models, and have presented the potential links between genes or proteins in the occurrence and development of tinnitus. Conclusion: The research on tinnitus-related genes is still in the exploratory stage, and further high-quality research evidence is needed. [ABSTRACT FROM AUTHOR]

Problem: Various etiological factors, such as infection and inflammation, may induce the adverse outcomes of pregnancy of miscarriage, stillbirth, or preterm birth. The pathogenic mechanisms associated with these adverse pregnancies are yet unclear. We hypothesized that a common pathogenic mechanism may underlie variant adverse outcomes of pregnancy, which are induced by genetic‐environmental factors. The specific objective of the current study is to uncover the common molecular mechanism(s) by identifying the specific transcripts that are present in variant subtypes of pregnancy loss and preterm birth. Method of Study: Transcriptomic profiling was performed with RNA expression microarray or RNA sequencing of placentas derived from pregnancy loss (which includes spontaneous miscarriage, recurrent miscarriage, and stillbirth) and spontaneous preterm birth, followed by bioinformatic analysis of multi‐omic integration to identify pathogenic molecules and pathways involved in pathological pregnancies. Results: The enrichment of common differentially expressed genes between full‐term birth and preterm birth and pregnancy loss of miscarriage and stillbirth revealed different pathophysiological pathway(s), including cytokine signaling dysregulated in spontaneous preterm birth, defense response, graft‐versus‐host disease, antigen processing and presentation, and T help cell differentiation in spontaneous miscarriage. Thirty‐three genes shared between spontaneous preterm birth and spontaneous miscarriage were engaged in pathways of interferon gamma–mediated signaling and of antigen processing and presentation. For spontaneous miscarriage, immune response was enriched in the fetal tissue of chorionic villi and in the maternal facet of the placental sac. The transcript of nerve growth factor receptor was identified as the common molecule that is differentially expressed in all adverse pregnancies: spontaneous preterm birth, stillbirth, spontaneous miscarriage, and recurrent miscarriage. Superoxide dismutase 2 was up‐regulated in all adverse outcomes of pregnancy except for recurrent miscarriage. Cytokine‐cytokine receptor interaction was the common pathway in spontaneous preterm birth and spontaneous miscarriage. Defense response was enriched in the fetal tissue of miscarriage and in the maternal tissue in spontaneous miscarriage. Conclusions: Our results indicated that the chemokine‐cytokine pathway may play important roles in and function as a common pathogenic mechanism associated with, the different adverse outcomes of pregnancy, which demonstrated that differentially expressed transcripts could result from a common pathogenic mechanism associated with pregnancy loss and spontaneous preterm birth, although individual pregnancy outcomes may differ from each other phenotypically. [ABSTRACT FROM AUTHOR]

Background: During intrauterine development, the formation and function of synaptic vesicles (SVs) are thought to be fundamental conditions essential for normal development of the brain. Lacking advanced technology during the intrauterine period, such as longitudinal real-time monitoring of the SV-associated transcripts (SVATs), which include six pairs of lncRNA-mRNA, has limited acquisition of the dynamic gene expression profile (GEP) of SVATs. We previously reported the differential expression of SVATs in the peripheral blood of autistic children. The current study was designed to determine the dynamic profiles of differentially-expressed SVATs in circulating exosomes (EXs) derived from autistic children and pregnant women at different gestational ages.Methods: Blood samples were collected from autistic children and women with variant physiopathologic pregnancies. EXs were isolated with an ExoQuick Exosome Precipitation Kit and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. The expression of lncRNAs and lncRNA-targeted mRNAs were quantified using real-time PCR.Results: SVAT-associated lncRNAs-mRNAs were detected in autistic children and differentially expressed from the first trimester of pregnancy to the term of delivery. Pathologic pregnancies, including spontaneous preterm birth (sPTB), preeclampsia (PE), and gestational diabetes mellitus (GDM), were compared to normal physiologic pregnancies, and shown to exhibit specific correlations between SVAT-lncRNA and SVAT-mRNA of STX8, SLC18A2, and SYP with sPTB; SVAT-lncRNA and SVAT-mRNA of STX8 with PE; and SVAT-lncRNA and SVAT-mRNA of SV2C as well as SVAT-mRNA of SYP with GDM.Conclusion: Variant complications in pathologic pregnancies may alter the GEP of SVATs, which is likely to affect the intrauterine development of neural circuits and consequently influence fetal brain development. [ABSTRACT FROM AUTHOR]

Aim: Several studies have examined the links between maternal obesity and the risk of cerebral palsy (CP) in children, with inconsistent results. The aim of our study was to investigate whether maternal obesity is associated with increased risk of CP in offspring by using meta-analysis.Method: PubMed and Web of Science were searched until August 2017. Observational studies relevant to the maternal obesity and risk of CP in children were extracted and compiled. Meta-analyses were performed for different obesity levels and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were reported.Results: A total of five cohort studies involving 12 324 cases and 7 919 288 participants were included in our meta-analysis. The pooled crude and adjusted ORs (95% CIs) were 1.65 (1.38-1.98) and 1.51 (1.24-1.84) respectively. Additionally, the pooled OR (95% CI) for CP in offspring in relation to maternal obesity class I (body mass index [BMI] 30.0-34.9), class II (BMI 35.0-39.9), and class III (BMI≥40.0) compared with normal weight during prepregnancy or pregnancy was 1.31 (1.15-1.50), 1.65 (1.34-2.02), and 2.37 (1.91-2.94) respectively.Interpretation: This meta-analysis demonstrated that increasing grades of maternal obesity are associated with a higher risk of CP in offspring.What This Paper Adds: Meta-analysis demonstrates a significant positive association between maternal obesity and the risk of cerebral palsy (CP) in children. Subgroup analysis indicates that higher grades of maternal obesity are associated with increasing risk of CP. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to determine the cervical calreticulin and cathepsin-G concentrations in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) with respect to the presence of microbial invasion of the amniotic cavity (MIAC) and intra-amniotic inflammation (IAI).Methods: Eighty women with singleton pregnancies complicated by PPROM were included in this study. Cervical and amniotic fluids were obtained at the time of admission, and concentrations of calreticulin and cathepsin-G in cervical fluid were determined using ELISA. The MIAC was defined as a positive PCR analysis for Ureaplasma species, Mycoplasma hominis, and/or Chlamydia trachomatis and/or by positivity for the 16S rRNA gene. IAI was defined as amniotic fluid bedside IL-6 concentrations ≥745 pg/mL Result: Neither women with MIAC nor with IAI had different cervical fluid concentrations of calreticulin (with MIAC: median 18.9 pg/mL vs. without MIAC: median 14.7 pg/mL, p = 0.28; with IAI: median 14.3 pg/mL vs. without IAI: median 15.6 pg/mL, p = 0.57;) or of cathepsin-G (with MIAC: median 30.7 pg/mL vs. without MIAC: median 24.7 pg/mL, p = 0.28; with IAI: median 27.3 pg/mL vs. without IAI: median 25.1 pg/mL, p = 0.80) than women without those complications. No associations between amniotic fluid IL-6 concentrations, gestational age at sampling, and cervical fluid calreticulin and cathepsin-G concentrations were found.Conclusions: Cervical fluid calreticulin and cathepsin-G concentrations did not reflect the presence of MIAC or IAI in women with PPROM. [ABSTRACT FROM AUTHOR]

Objective: Despite decades of research on risk indicators of spontaneous preterm birth (PTB), reliable biomarkers are still not available to screen or diagnose high-risk pregnancies. Several biomarkers in maternal and fetal compartments have been mechanistically linked to PTB, but none of them are reliable predictors of pregnancy outcome. This systematic review was conducted to synthesize the knowledge on PTB biomarkers identified using multiplex analysis. Materials and methods: Three electronic databases (PubMed, EMBASE and Web of Science) were searched for studies in any language reporting the use of multiplex assays for maternal biomarkers associated with PTB published from January 2005 to March 2014. Results: Retrieved citations (3631) were screened, and relevant studies (33) were selected for full-text reading. Ten studies were included in the review. Forty-two PTB-related proteins were reported, and RANTES and IL-10 (three studies) followed by MIP-1β, GM-CSF, Eotaxin, and TNF-RI (two studies) were reported more than once in maternal serum. However, results could not be combined due to heterogeneity in type of sample, study population, assay, and analysis methods. Conclusion: By this systematic review, we conclude that multiplex assays are a potential technological advancement for identifying biomarkers of PTB, although no single or combination of biomarkers could be identified to predict PTB risk. [ABSTRACT FROM AUTHOR]

Problem We have previously determined that long non-coding RNAs (lnc RNAs) are differentially expressed in preterm premature rupture of membranes ( PPROM) and hypothesized that the collagenolysis ubiquitin-proteasome system may be activated by infection and inflammation. However, direct evidence of the involvement of lnc RNAs in transcriptional and posttranscriptional regulation of the infection-triggered alteration of collagen is lacking. Method of study A previously developed mouse model with MHV68 viral infection was assessed to determine whether viral infection may induce differential expression of lnc RNAs in mouse placentas and amniotic sacs. Results Differential expression of lnc RNAs that are associated with collagen was found in HMV68 viral-infected, compared to non-infected, mouse placentas and amniotic sacs. Differential expression of messenger RNAs ( mRNAs) of collagen was also documented. Conclusions Our data demonstrate, for the first time, that viral infection may induce the differential expression of lnc RNAs that are associated with collagen. Based on this finding, we propose that lnc RNA may have involved in regulating of infection-induced collagen transcription. [ABSTRACT FROM AUTHOR]

[Display omitted] • This is the largest nationwide study to examine the associations of maternal PM 2.5 exposure with PROM in China. • Both acute and chronic maternal ambient PM 2.5 exposure increased the risk of PROM. • Women who were less educated, obese, or delivered in a cold season were more sensitive to PM 2.5 exposure. Prelabor rupture of the fetal membranes (PROM) is a major contributor to adverse perinatal outcomes. Some epidemiologic studies explored the association between maternal PM 2.5 exposure and PROM but failed to treat the labor induction and prelabor cesarean section as censored observations. We aimed to evaluated whether acute and chronic maternal ambient PM 2.5 exposure may increase the risk of PROM in China. This study was based on the China Labor and Delivery Survey, a nationwide multicenter investigation. Included in the current analysis were 45,879 singleton spontaneous births in 96 hospitals in mainland China from 2015 to 2017. Outcomes were PROM, preterm PROM (<37 weeks' gestation) and term PROM (≥37 weeks' gestation). Daily concentration of PM 2.5 at 1 km spatial resolution was estimated by gap-filling model. Generalized linear mixed model and mixed effects Cox model were applied to assess the associations of acute (from 0 to 4 days before delivery) and chronic (average gestational and trimester-specific) ambient PM 2.5 exposure with outcomes, respectively. Significant associations were found between acute PM 2.5 exposures (per interquartile range increase) and the risk of preterm PROM (OR = 1.11; 95 % CI: 1.03, 1.19 for PM 2.5 on delivery day; OR = 1.10; 95 % CI: 1.02, 1.18 for PM 2.5 1 day before delivery) but not for term PROM. An interquartile range increase in PM 2.5 during the second trimester was associated with elevated risks of PROM (HR = 1.14; 95 % CI: 1.07, 1.22), preterm PROM (HR = 1.22; 95 % CI: 1.02, 1.45) and term PROM (HR = 1.13; 95 % CI: 1.06, 1.22), respectively. Women who were less educated, obese, or gave birth in a cold season appeared to be more sensitive to ambient PM 2.5 exposure. Our findings suggest that both acute and chronic maternal exposures to ambient PM 2.5 during pregnancy are risk factors for PROM. [ABSTRACT FROM AUTHOR]

Problem Spontaneous abortion ( SA) occurs before 20 gestational weeks. Approximately, half of recurrent SA has no identifiable cause. No report has yet been investigated the possible involvement of lnc RNA in pregnancy loss. Method of Study Sixteen pairs of pregnancies with spontaneous abortions ( SA) and induced abortions ( IA) were studied. Embryonic sacs and decidua were collected for each pregnancy. A Human Lnc RNA Array was employed to profile genomewide lnc RNAs, which were then validated by RT- PCR. Results Differentially expressed lnc RNAs were identified. Biological pathways were categorized into six major groups: infection and inflammation, metabolism, signaling and transcriptional regulation, smooth muscle contraction, cell process, and coagulation. Conclusions Infection and inflammation pathways regulated by lnc RNAs were determined as the predominant pathogenetic factors underlying the SA. Finding that antisense lnc RNAs have been either up- or down-regulated suggests that they may have both cis- and trans-regulations. [ABSTRACT FROM AUTHOR]

Unlabelled: It has been hypothesized that dysregulation of brain-expressed genes is the major predisposing underlying mechanism for autism. This dysregulation may be mediated by differential methylation of CpG sites within gene promoters, which could be candidate biomarkers and used for early clinical screening of autism. A total of 131 pairs of age- and sex-matched autistic and control subjects were recruited in this study. Peripheral blood cells were analyzed. The first five pairs were randomly applied to array-based genome-wide methylation studies. A neuron-specific gene, ENO2, was found to be hypermethylated in the autistic samples. This difference was validated by bisulfite sequencing PCR (BSP). The differential expression of ENO2 gene was further analyzed with RT-qPCR and ELISA. The hypermethylation of ENO2 within the promoter region was confirmed by BSP to be present in 14.5 % (19/131) of the total of the autistic samples. The mean ENO2 RNA level in these 19 autistic samples was reduced by about 70 % relative to that in controls. The average level of ENO2 protein expression in the 19 autistic samples (15.18 ± 3.51 μg/l) was about half of that in the controls (33.86 ± 8.16 μg/l).Conclusion: These findings suggest that reduced ENO2 expression may be a biomarker for a subset of autistic children. [ABSTRACT FROM AUTHOR]

It has been hypothesized that dysregulation of brain-expressed genes is the major predisposing underlying mechanism for autism. This dysregulation may be mediated by differential methylation of CpG sites within gene promoters, which could be candidate biomarkers and used for early clinical screening of autism. A total of 131 pairs of age- and sex-matched autistic and control subjects were recruited in this study. Peripheral blood cells were analyzed. The first five pairs were randomly applied to array-based genome-wide methylation studies. A neuron-specific gene, ENO2, was found to be hypermethylated in the autistic samples. This difference was validated by bisulfite sequencing PCR (BSP). The differential expression of ENO2 gene was further analyzed with RT-qPCR and ELISA. The hypermethylation of ENO2 within the promoter region was confirmed by BSP to be present in 14.5 % (19/131) of the total of the autistic samples. The mean ENO2 RNA level in these 19 autistic samples was reduced by about 70 % relative to that in controls. The average level of ENO2 protein expression in the 19 autistic samples (15.18 ± 3.51 μg/l) was about half of that in the controls (33.86 ± 8.16 μg/l). Conclusion: These findings suggest that reduced ENO2 expression may be a biomarker for a subset of autistic children. [ABSTRACT FROM AUTHOR]

Background: Preconception care is defined as the promotion of the health and well-being of a woman and her partner before pregnancy. Improving preconception health can result in improved reproductive health outcomes. China has issued latest version official guideline for preconception care in 2011. The objective of this cross-sectional study is to determine whether there is a variation in the quality of preconception healthcare services in distinct eastern and northern populations of China, and what factors are associated with such variation. Methods: A cross-sectional survey using our previously developed preconception instrument was conducted. Women at reproductive age planning for pregnancy were surveyed along with their partners at hospitals during their pre-pregnancy health examination. Data collected include general health/life profiles, pregnancy history, alcohol/tobacco/drug exposures, immunizations, micronutrient supplements and the demands in preconception care. After quality assessment, statistical analysis were applied to evaluate the variations in preconception factors between people from Hebei and Jiangsu Provinces. Results: 3202 women of reproductive age in from eastern province, Jiangsu, and in a northern province, Hebei, participated this study. 2806 of them and their partners have completed the questionnaire, at a rate of 87.6%, 1011 were from Jiangsu and 1795 were from Hebei. Statistical significance was obtained for maternal age (P < 0.001), body mass index (u =13.590, P <0.001), education (χ² = 916.33, P < 0.001), occupation (χ² = 901.78, P < 0.001), health status/common disease, immunization status, and need for preconception care. Conclusions: For a country as large as China, the centralized guideline for standardized preconception healthcare does have a very crucial positive role in reproductive healthcare, but it may not be suited for all populations. Regional authorities should consider the demographics and healthcare needs of the local population and modify the centralized guideline accordingly, as well as provide a better education and professional services for the public, to improve the quality of preconception services at both the regional and the national level. [ABSTRACT FROM AUTHOR]

Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB. [ABSTRACT FROM AUTHOR]

Abstract: The Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease characterized by segmental premature aging. Applying a two-dimensional chromatographic proteomic approach, the 2D Protein Fractionation System (PF2D), we identified 30 differentially expressed proteins in cultured HGPS fibroblasts. We categorized them into five groups: methylation, calcium ion binding, cytoskeleton, duplication, and regulation of apoptosis. Among these 30 proteins, 23 were down-regulated, while seven were up-regulated in HGPS fibroblasts as compared to normal fibroblasts. Three differentially expressed cytoskeleton proteins, vimentin, actin, and tubulin, were validated via Western blotting and characterized by immunostaining that revealed densely thickened bundles and irregular structures. Furthermore in the HGPS cells, the cell cycle G1 phase was elongated and the concentration of free cytosolic calcium was increased, suggesting intracellular retention of calcium. The results that we obtained have implications for understanding the aging process. [Copyright &y& Elsevier]

Abstract: The neuronal ceroid lipofuscinoses (NCLs) are a group of neuronal degenerative diseases that primarily affect children. Previously we hypothesized that the similarity of the phenotypes among the variant subtypes of NCL suggests that the NCLs share a common metabolic functional pathway. To test our hypothesis, we have studied several candidate proteins identified using a proteomic approach. We analyzed their differential expression and cataloged their functions and involved pathways. Forty protein peaks, differentially expressed in NCLs, were selected from two-dimensional protein fragmentation (PF2D) maps and twenty-four proteins were identified by MALDI-TOF-MS or LC–ESI-MS/MS. Six proteins were verified by further Western blotting. Our results showed that annexin A1, annexin A2, and vimentin were significantly down-regulated in NCL1, NCL2, NCL3, and NCL8 cells; galectin-1 was down-regulated in NCL1, NCL3, and NCL8 but up-regulated in NCL2 cells; and isoform 5 of caldesmon was up-regulated in all NCL cell types. The histone 2B was down-regulated in NCL3. Functional analysis showed that the differentially expressed proteins identified by PF2D could be grouped into categories of intermediate filaments, cell motility, apoptosis, cytoskeleton, membrane trafficking, calcium binding, nucleosome assembly, pigment granule and cell development. Immunocytochemistry revealed nuclear translocalization of annexin A1 in CLN2-deficient fibroblasts and abnormal distribution of l-caldesmon in cultured CLN1, CLN2, CLN3 and CLN8-deficient fibroblasts. Finding differentially expressed proteins in variant NCLs, which showed disturbances of cytoskeleton, RAGE-dependent cellular pathways and decreased glycolysis provides evidence supporting our hypothesis. These findings may contribute to the discovery of molecular biomarkers and may help further elucidate the pathogenic mechanisms underlying the NCLs. [Copyright &y& Elsevier]

Abstract: PCBP1 is a member of the hnRNP family and participates in the regulation of transcription and translation. Previously, we identified transcripts targeted by overexpression of exogenous PCBP1. To further determine if these altered transcripts may also be targeted by a lack of PCBP1, we depleted endogenous PCBP1 in human SH-SY5Y cells. We identified 941 transcripts with the Affymetrix and 1362 with the Agilent expression platforms. There were 375 transcripts identified by both platforms, including 328 down-regulated and 47 up-regulated. The identified transcripts could be grouped into neuronal, cell signaling, metabolic, developmental, and differentiation categories, with pathway involvement in Wnt signaling, TGF beta signaling, translation factors and nuclear receptors. A proteomic profiling study with a two-dimensional chromatographic platform showed global translational changes over a range of isoelectric points (pI)=4.84–8.42. This study identifies the transcripts affected by knock-down of endogenous PCBP1 and compares them to the transcripts affected by overexpression of PCBP1. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Genetic factors play a critical role in the etiology of bipolar disorder (BPAD). Previous studies suggested an association between thyroid dysfunction and BPAD. We hypothesize that genetic variations in the type II deiodinase (DIO2) gene that possibly alter the bioactivity of thyroid hormones are associated with BPAD. Method: A case–control association study was conducted in a subset of Chinese Han population. Two single nucleotide polymorphisms (SNP), open reading frame a (ORFa)-Gly3Asp (rs12885300) and Thr92Ala (rs225014) with potential functions on the activity of DIO2, were selected. The frequencies of allele, genotype and haplotype of the two SNPs were compared between the BPAD patients and the control group. Results: Statistical significance between the BPAD patients and the control group was observed for the allele (χ 2 =7.746, P =0.005, df =1) and genotype frequencies (χ 2 =8.158, P =0.017, df =2) at the locus of ORFa-Gly3Asp, and for the allele (χ 2 =15.838, P =7.00e−005, df =1) and genotype frequencies (χ 2 =17.236, P =0.0002, df =2) at Thr92Ala. Distribution of allele 3Gly and 92Ala were significantly higher in the BPAD patients, with odds ratios of 1.489 [95% confidence interval (CI)=1.124–1.973] and 1.616 [95% CI=1.275–2.048], respectively. Individuals with two copies of the variant 3Gly or 92Ala were at greater risk of BPAD than individuals with one copy (dose–response manner). Haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for BPAD with odds ratios of 3.759 (95% CI=2.013–7.020) and 1.292 (95% CI=1.017–1.642), respectively, while ORFa-3Asp-92Thr probably played a protective role with an odds ratio of 0.395 (95% CI=0.284–0.549). Conclusion: Data generated from this study supported our hypothesis that genetic variations of the DIO2 gene were associated with BPAD and suggested further consideration on the possible involvement of these functionally active variants in the pathophysiology of BPAD. [Copyright &y& Elsevier]

Abstract: Progesterone plays an important role in the regulation of normal endometrium function by binding to progesterone receptor (PR). In endometrial cancer, however, PR is always down-regulated. Previous reports showed that methylation in the promoter region of the PR gene may be responsible for PRB isoform repression. However, the CpG islands in the exon region of the PR gene are much richer and longer than in the promoter region. We hypothesize that methylation in the exon region may also take part in the down-regulation of the PR gene. The methylation status of the first exon of the PR gene in endometrial cell cultures was investigated. Aberrant methylation patterns were observed in the first exon of PR gene, and the methylation density is correlated with the differentiation of different types of endometrial cancer cells. DNA methyltransferase (DNMT) and histone deacetylase inhibitor 5-aza-2′-deoxycytidine (ADC), as well as trichostatin A (TSA), which reverses PR gene expression, were also studied. A combination of ADC and TSA resulted in synergistic effects in inducing PR expression, down-regulation of DNMT1 and DNMT3A, and could also have antigrowth effect on endometrial cancer cells by inducing apoptosis. [Copyright &y& Elsevier]

• Multiomics were applied to study premature utero-contraction in sPTB. • Genomic variants in the sarcomere gene TTN were identified in sPTB. • Epigenetic regulation of long non-coding RNAs were identified in gene TPM3. • Methylomic profiles were identified in sarcomeric genes/loci. • Differential expression of transcripts associates with premature utero-contraction. Spontaneous preterm birth is a syndrome with clinical and genetic heterogeneity. Few studies have focused on the genetic and epigenetic defects and pathogenic mechanisms associated with premature uterine contraction in spontaneous preterm birth. The objective of this study was to investigate the (epi)genetic variations associated with premature uterine contraction of spontaneous preterm birth. A systems biology approach with an integrated multiomic study was employed. Biobanked pregnancy tissues selected from a pregnancy cohort were subjected to genomic, transcriptomic, methylomic, and proteomic studies, with a focus on genetic loci/genes related to uterine muscle contraction, specifically, genes associated with sarcomeres and desmosomes. Thirteen single nucleotide variations and pathogenic variants were identified in the sarcomere gene, TTN , which encodes the protein Titin, from 146 women with spontaneous preterm labor. Differential expression profiles of five long non-coding RNAs were identified from loci that overlap with four sarcomeric genes. Longitudinally, the long non-coding RNA of gene TPM3 that encodes the protein tropomysin 3 was found to significantly regulate the mRNA of TPM3 in the placenta, compared to maternal blood. The majority of genome methylation profiles related to premature uterine contraction were also identified in the CpG promoters of sarcomeric genes/loci. Differential expression profiles of mRNAs associated with premature uterine contraction showed 22 genes associated with sarcomeres and three with desmosomes. The results demonstrated that premature uterine contraction was associated mainly with pathogenic variants of the TTN gene and with transcriptomic variations of sarcomeric premature uterine contraction genes. This association is likely regulated by epigenetic factors, including methylation and long non-coding RNAs. [ABSTRACT FROM AUTHOR]

Background: Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients.Results: Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery.Conclusions: We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the stillbirth rate in China.